Chronic high-dosage fish oil exacerbates gut-liver axis injury in alcoholic steatohepatitis in mice: the roles of endotoxin and IL-4 in Kupffer cell polarization imbalance.
In the present study, intestinal tight junctions (TJs) and Kupffer cell polarization were investigated in an alcoholic steatohepatitis (ASH) mouse model to uncover the potential side effects of overexposure to fish oil or omega-3 fatty acids. The mice were fed ad libitum with a liquid diet containing ethanol and fish oil. In the meantime, ethanol was given every 5-7 days by gavage to simulate binge drinking. After the 7th binge, steatosis, necrosis, inflammatory infiltration, and bridging fibrosis were observed in the liver by histological staining. After the 13th binge, the inducers, markers and other downstream genes/proteins of the Kupffer cell M1/M2 phenotype in the liver, serum, and small intestine were analysed. The results suggested that a chronic high dosage of fish oil alone reduced the mRNA levels of most genes tested and showed a tendency to damage the intestinal zonula occludens-1 localization and reduce the number of M2 Kupffer cells. Meanwhile, the combination of fish oil and ethanol damaged the intestinal TJs, resulting in an increased endotoxin level in the liver. Gut-derived endotoxin polarized Kupffer cells to the M1 phenotype, whereas the number of cells with the M2 phenotype (markers: CD163 and CD206) was decreased. Interleukin-4 (IL-4), an M2 Kupffer cell inducer, was also decreased. Moreover, in vitro experiments showed that IL-4 reversed eicosapentaenoic acid-induced CD163 and CD206 mRNA suppression in RAW 264.7 cells. Overall, our results showed that a chronic high dosage of fish oil exacerbated gut-liver axis injury in alcoholic liver disease in mice, and endotoxin/IL-4-induced Kupffer cell polarization imbalance might play an important role in that process.


The role of brain size on mammalian population densities.
The local abundance or population density of different organisms often varies widely. Understanding what determines this variation is an important, but not yet fully resolved question in ecology. Differences in population density are partly driven by variation in body size and diet among organisms. Here we propose that the size of an organism' brain could be an additional, overlooked, driver of mammalian population densities. We explore two possible contrasting mechanisms by which brain size, measured by its mass, could affect population density. First, because of the energetic demands of larger brains and their influence on life history, we predict mammals with larger relative brain masses would occur at lower population densities. Alternatively, larger brains are generally associated with a greater ability to exploit new resources, which would provide a competitive advantage leading to higher population densities among large-brained mammals. We tested these predictions using phylogenetic path analysis, modelling hypothesized direct and indirect relationships between diet, body mass, brain mass and population density for 656 non-volant terrestrial mammalian species. We analysed all data together and separately for marsupials and the four taxonomic orders with most species in the dataset (Carnivora, Cetartiodactyla, Primates, Rodentia). For all species combined, a single model was supported showing lower population density associated with larger brains, larger bodies and more specialized diets. The negative effect of brain mass was also supported for separate analyses in Primates and Carnivora. In other groups (Rodentia, Cetartiodactyla and marsupials) the relationship was less clear: supported models included a direct link from brain mass to population density but 95% confidence intervals of the path coefficients overlapped zero. Results support our hypothesis that brain mass can explain variation in species' average population density, with large-brained species having greater area requirements, although the relationship may vary across taxonomic groups. Future research is needed to clarify whether the role of brain mass on population density varies as a function of environmental (e.g. environmental stability) and biotic conditions (e.g. level of competition).


Regulation of the Germinal Center Reaction and Somatic Hypermutation Dynamics by Homologous Recombination.
During somatic hypermutation (SHM) of Ig genes in germinal center B cells, lesions introduced by activation-induced cytidine deaminase are processed by multiple error-prone repair pathways. Although error-free repair by homologous recombination (HR) is crucial to prevent excessive DNA strand breakage at activation-induced cytidine deaminase off-target genes, its role at the hypermutating Ig locus in the germinal center is unexplored. Using B cell-specific inactivation of the critical HR factor Brca2, we detected decreased proliferation, survival, and thereby class switching of ex vivo-activated B cells. Intriguingly, an HR defect allowed for a germinal center reaction and affinity maturation in vivo, albeit at reduced amounts. Analysis of SHM revealed that a certain fraction of DNA lesions at C:G bp was indeed repaired in an error-free manner via Brca2 instead of being processed by error-prone translesion polymerases. By applying a novel pseudo-time in silico analysis of mutational processes, we found that the activity of A:T mutagenesis during SHM increased during a germinal center reaction, but this was in part defective in Brca2-deficient mice. These mutation pattern changes in Brca2-deficient B cells were mostly specific for the Ig V region, suggesting a local or time-dependent need for recombination repair to survive high rates of SHM and especially A:T mutagenesis.


Analysis of the circadian transcriptome of the Antarctic krill Euphausia superba.
Antarctic krill (Euphausia superba) is a high latitude pelagic organism which plays a central role in the Southern Ocean ecosystem. E. superba shows daily and seasonal rhythms in physiology and behaviour, which are synchronized with the environmental cycles of its habitat. Recently, the main components of the krill circadian machinery have been identified and characterized. However, the exact mechanisms through which the endogenous timing system operates the control and regulation of the overt rhythms remains only partially understood. Here we investigate the involvement of the circadian clock in the temporal orchestration of gene expression by using a newly developed version of a krill microarray platform. The analysis of transcriptome data from krill exposed to both light-dark cycles (LD 18:6) and constant darkness (DD), has led to the identification of 1,564 putative clock-controlled genes. A remarkably large proportion of such genes, including several clock components (clock, period, cry2, vrille, and slimb), show oscillatory expression patterns in DD, with a periodicity shorter than 24 hours. Energy-storage pathways appear to be regulated by the endogenous clock in accordance with their ecological relevance in daily energy managing and overwintering. Our results provide the first representation of the krill circadian transcriptome under laboratory, free-running conditions.


Age-specific probability of live birth with oocyte cryopreservation: an individual patient data meta-analysis.
To estimate age-specific probabilities of live birth with oocyte cryopreservation in nondonor (ND) egg cycles. Individual patient data meta-analysis. Assisted reproduction centers. Infertile patients undergoing ND mature oocyte cryopreservation. PubMed was searched for clinical studies on oocyte cryopreservation from January 1996 through July 2011. Randomized and nonrandomized studies that used ND frozen-thawed mature oocytes with pregnancy outcomes were included. Authors of eligible studies were contacted to obtain individual patient data. Live birth probabilities based on age, cryopreservation method, and the number of oocytes thawed, injected, or embryos transferred. Original data from 10 studies including 2,265 cycles from 1,805 patients were obtained. Live birth success rates declined with age regardless of the freezing technique. Despite this age-induced compromise, live births continued to occur as late as ages 42 and 44 years with slowly frozen and vitrified oocytes, respectively. Estimated probabilities of live birth for vitrified oocytes were higher than those for slowly frozen. The live birth probabilities we calculated would enable more accurate counseling and informed decisions for infertile women considering oocyte cryopreservation. Given the success probabilities, we suggest that policy makers should consider oocyte freezing as an integral part of prevention and treatment of infertility.


Regional synthesis of Mediterranean atmospheric circulation during the Last Glacial Maximum.
Atmospheric circulation leaves few direct traces in the geological record, making reconstructions of this crucial element of the climate system inherently difficult. We produced a regional Mediterranean synthesis of paleo-proxy data from the sea surface to alpine altitudes. This provides a detailed observational context for change in the three-dimensional structure of atmospheric circulation between the Last Glacial Maximum (LGM, approximately 23,000 to 19,000 years ago) and the present. The synthesis reveals evidence for frequent cold polar air incursions, topographically channeled into the northwestern Mediterranean. Anomalously steep vertical temperature gradients in the central Mediterranean imply local convective precipitation. We find the LGM patterns to be analogous, though amplified, to previously reconstructed phases of enhanced meridional winter circulation during the Maunder Minimum (the Little Ice Age).


Adult congenital heart disease training in Europe: current status, disparities and potential solutions.
This study aimed to determine the status of training of adult congenital heart disease (ACHD) cardiologists in Europe. A questionnaire was sent to ACHD cardiologists from 34 European countries. Representatives from 31 of 34 countries (91%) responded. ACHD cardiology was recognised by the respective ministry of Health in two countries (7%) as a subspecialty. Two countries (7%) have formally recognised ACHD training programmes, 15 (48%) have informal (neither accredited nor certified) training and 14 (45%) have very limited or no programme. Twenty-five countries (81%) described training ACHD doctors 'on the job'. The median number of ACHD centres per country was 4 (range 0-28), median number of ACHD surgical centres was 3 (0-26) and the median number of ACHD training centres was 2 (range 0-28). An established exit examination in ACHD was conducted in only one country (3%) and formal certification provided by two countries (7%). ACHD cardiologist number versus gross domestic product Pearson correlation coefficient=0.789 (p<0.001). Formal or accredited training in ACHD is rare among European countries. Many countries have very limited or no training and resort to 'train people on the job'. Few countries provide either an exit examination or certification. Efforts to harmonise training and establish standards in exit examination and certification may improve training and consequently promote the alignment of high-quality patient care.


Multilayer Patterning of High Resolution Intrinsically Stretchable Electronics.
Stretchable electronics can bridge the gap between hard planar electronic circuits and the curved, soft and elastic objects of nature. This has led to applications like conformal displays, electronic skin and soft neuroprosthetics. A remaining challenge, however, is to match the dimensions of the interfaced systems, as all require feature sizes well below 100 μm. Intrinsically stretchable nanocomposites are attractive in this context as the mechanical deformations occur on the nanoscale, although methods for patterning high performance materials have been lacking. Here we address these issues by reporting on a multilayer additive patterning approach for high resolution fabrication of stretchable electronic devices. The method yields highly conductive 30 μm tracks with similar performance to their macroscopic counterparts. Further, we demonstrate a three layer micropatterned stretchable electroluminescent display with pixel sizes down to 70 μm. These presented findings pave the way towards future developments of high definition displays, electronic skins and dense multielectrode arrays.


Acrocyanosis as a side effect of tricyclic antidepressants: a case report.
Acrocyanosis is probably the most unusual side effect of tricyclic antidepressant drugs. In this paper, we report a 10-year-old boy with primary enuresis nocturna and attention deficit hyperactivity disorder who developed two episodes of acrocyanosis, the first of which was after imipramine treatment and the second after desipramine usage. We also review the possible pathogenesis of acrocyanosis. We suggest that physicians should be aware of this rare side effect of tricyclic antidepressants.


Global change and ecosystem connectivity: How geese link fields of central Europe to eutrophication of Arctic freshwaters.
Migratory connectivity by birds may mutually affect different ecosystems over large distances. Populations of geese overwintering in southern areas while breeding in high-latitude ecosystems have increased strongly over the past decades. The increase is likely due to positive feedbacks caused by climate change at both wintering, stopover sites and breeding grounds, land-use practices at the overwintering grounds and protection from hunting. Here we show how increasing goose populations in temperate regions, and increased breeding success in the Arctic, entail a positive feedback with strong impacts on Arctic freshwater ecosystems in the form of eutrophication. This may again strongly affect community composition and productivity of the ponds, due to increased nutrient loadings or birds serving as vectors for new species.


Influence of age, site, and degenerative state on the speed of sound in equine articular cartilage.
To determine the speed of sound (SOS) in equine articular cartilage and investigate the influence of age, site in the joint, and cartilage degeneration on the SOS. Cartilage samples from 38 metacarpophalangeal joints of 38 horses (age range, 5 months to 22 years). Osteochondral plugs were collected from 2 articular sites of the proximal phalanx after the degenerative state was characterized by use of the cartilage degeneration index (CDI) technique. The SOS was calculated (ratio of needle-probe cartilage thickness to time of flight of the ultrasound pulse), and relationships between SOS value and age, site, and cartilage degeneration were evaluated. An analytical model of cartilage indentation was used to evaluate the effect of variation in true SOS on the determination of cartilage thickness and dynamic modulus with the ultrasound indentation technique. The mean SOS for all samples was 1,696 +/- 126 m/s. Age, site, and cartilage degeneration had no significant influence on the SOS in cartilage. The analytical model revealed that use of the mean SOS of 1,696 m/s was associated with maximum errors of 17.5% on cartilage thickness and 70% on dynamic modulus in an SOS range that covered 95% of the individual measurements. In equine articular cartilage, use of mean SOS of 1,696 m/s in ultrasound indentation measurements introduces some inaccuracy on cartilage thickness determinations, but the dynamic modulus of cartilage can be estimated with acceptable accuracy in horses regardless of age, site in the joint, or stage of cartilage degeneration.


Resolving the organization of the territory of the third visual area: a new proposal.
In primates, the cortex adjoining the rostral border of V2 has been variously interpreted as belonging to a single visual area, V3, with dorsal V3 (V3d) representing the lower visual quadrant and ventral V3 (V3v) representing the upper visual quadrant, V3d and V3v constituting separate, incomplete visual areas, V3d and ventral posterior (VP), or V3d being divided into several visual areas, including a dorsomedial (DM) visual area, a medial visual area (M), and dorsal extension of VP (or VLP). In our view, the evidence from V1 connections strongly supports the contention that V3v and V3d are parts of a single visual area, V3, and that DM is a separate visual area along the rostral border of V3d. In addition, the retinotopy revealed by V1 connection patterns, microelectrode mapping, optical imaging mapping, and functional magnetic resonance imaging (fmri) mapping indicates that much of the proposed territory of V3d corresponds to V3. Yet, other evidence from microelectrode mapping and anatomical connection patterns supports the possibility of an upper quadrant representation along the rostral border of the middle of dorsal V2 (V2d), interpreted as part of DM or DM plus DI, and along the midline end of V2d, interpreted as the visual area M. While the data supporting these different interpretations appear contradictory, they also seem, to some extent, valid. We suggest that V3d may have a gap in its middle, possibly representing part of the upper visual quadrant that is not part of DM. In addition, another visual area, M, is likely located at the DM tip of V3d. There is no evidence for a similar disruption of V3v. For the present, we favor continuing the traditional concept of V3 with the possible modification of a gap in V3d in at least some primates.


Arsenic in the human food chain: the Latin American perspective.
Many regions of Latin America are widely reported for the occurrence of high arsenic (As) in groundwater and surface water due to a combination of geological processes and/or anthropogenic activities. In this paper, we review the available literature (both in English and Spanish languages) to delineate human As exposure pathways through the food chain. Numerous studies show that As accumulations in edible plants and crops are mainly associated with the presence of high As in soils and irrigation waters. However, factors such as As speciation, type and composition of soil, and plant species have a major control on the amount of As uptake. Areas of high As concentrations in surface water and groundwater show high As accumulations in plants, fish/shellfish, livestock meat, milk and cheese. Such elevated As concentrations in food may result in widespread health risks to local inhabitants, including health of indigenous populations and residents living close to mining industries. Some studies show that As can be transferred from the water to prepared meals, thereby magnifying the As content in the human diet. Arsenic speciation might also change during food preparation, especially during high temperature cooking, such as grilling and frying. Finally, the review of the available literature demonstrates the necessity of more rigorous studies in evaluating pathways of As exposure through the human food chain in Latin America.


Engineering ultrasmall water-soluble gold and silver nanoclusters for biomedical applications.
Gold and silver nanoclusters or Au/Ag NCs with core sizes smaller than 2 nm have been an attractive frontier of nanoparticle research because of their unique physicochemical properties such as well-defined molecular structure, discrete electronic transitions, quantized charging, and strong luminescence. As a result of these unique properties, ultrasmall size, and good biocompatibility, Au/Ag NCs have great potential for a variety of biomedical applications, such as bioimaging, biosensing, antimicrobial agents, and cancer therapy. In this feature article, we will first discuss some critical biological considerations, such as biocompatibility and renal clearance, of Au/Ag NCs that are applied for biomedical applications, leading to some design criteria for functional Au/Ag NCs in the biological settings. According to these biological considerations, we will then survey some efficient synthetic strategies for the preparation of protein- and peptide-protected Au/Ag NCs with an emphasis on our recent contributions in this fast-growing field. In the last part, we will highlight some potential biomedical applications of these protein- and peptide-protected Au/Ag NCs. It is believed that with continued efforts to understand the interactions of biomolecule-protected Au/Ag NCs with the biological systems, scientists can largely realize the great potential of Au/Ag NCs for biomedical applications, which could finally pave their way towards clinical use.


Educational attainment and HIV-1 infection in developing countries: a systematic review.
To assess whether educational status is associated with HIV-1 infection in developing countries by conducting a systematic review of published literature. Articles were identified through electronic databases and hand searching key journals. Studies containing appropriately analysed individual level data on the association between educational attainment and HIV-1 status in general population groups were included. Twenty-seven articles with appropriately analysed results from general population groups in developing countries were identified, providing information on only six countries. Large studies in four areas in Africa showed an increased risk of HIV-1 infection among the more educated, whilst among 21-year-old Thai army conscripts, longer duration of schooling was strongly protective against HIV infection. The association between education and schooling in Africa was stronger in rural areas and in older cohorts, but was similar in men and women. Serial prevalence studies showed little change in the association between schooling and HIV over time in Tanzania, but greater decreases in HIV prevalence among the more educated in Uganda, Zambia and Thailand. In Africa, higher educational attainment is often associated with a greater risk of HIV infection. However, the pattern of new HIV infections may be changing towards a greater burden among less educated groups. In Thailand those with more schooling remain at lower risk of HIV infection.


On the interaction of hyaluronic acid with synovial fluid lipid membranes.
All-atom molecular dynamics simulations have been used to investigate the adsorption of low molecular weight hyaluronic acid to lipid membranes. We have determined the interactions that govern the adsorption of three different molecular weight hyaluronic acid molecules (0.4, 3.8 & 15.2 kDa) to lipid bilayers that are representative of the surface-active phospholipid bilayers found in synovial joints. We have found that both direct hydrogen bonds and water-mediated interactions with the lipid headgroups play a key role in the binding of hyaluronic acid to the lipid bilayer. The water-mediated interactions become increasingly important in stabilising the adsorbed hyaluronic acid molecules as the molecular weight of hyaluronic acid increases. We also observe a redistribution of ions around bound hyaluronic acid molecules and the associated lipid headgroups, and that the degree of redistribution increases with the molecular weight of hyaluronic acid. By comparing this behaviour to that observed in simulations of the charge-neutral polysaccharide dextran (MW ∼ 15 kDa), we show that this charge redistribution leads to an increased alignment of the lipid headgroups with the membrane normal, and therefore to more direct and water-mediated interactions between hyaluronic acid and the lipid membrane. These findings provide a detailed understanding of the general structure of hyaluronic acid-lipid complexes that have recently been presented experimentally, as well as a potential mechanism for their enhanced tribological properties.


Carotid Wall Longitudinal Motion in Ultrasound Imaging: An Expert Consensus Review.
Motion extracted from the carotid artery wall provides unique information for vascular health evaluation. Carotid artery longitudinal wall motion corresponds to the multiphasic arterial wall excursion in the direction parallel to blood flow during the cardiac cycle. While this motion phenomenon has been well characterized, there is a general lack of awareness regarding its implications for vascular health assessment or even basic vascular physiology. In the last decade, novel estimation strategies and clinical investigations have greatly advanced our understanding of the bi-axial behavior of the carotid artery, necessitating an up-to-date review to summarize and classify the published literature in collaboration with technical and clinical experts in the field. Within this review, the state-of-the-art methodologies for carotid wall motion estimation are described, and the observed relationships between longitudinal motion-derived indices and vascular health are reported. The vast number of studies describing the longitudinal motion pattern in plaque-free arteries, with its putative application to cardiovascular disease prediction, point to the need for characterizing the added value and applicability of longitudinal motion beyond established biomarkers. To this aim, the main purpose of this review was to provide a strong base of theoretical knowledge, together with a curated set of practical guidelines and recommendations for longitudinal motion estimation in patients, to foster future discoveries in the field, toward the integration of longitudinal motion in basic science as well as clinical practice.


Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection.
Efficient maintenance of memory CD8 T cells is central to long-term protective immunity. IL-7- and IL-15-driven homeostatic proliferation is essential for long-term memory CD8 T cell persistence after acute infections. During chronic infections, however, virus-specific CD8 T cells respond poorly to these cytokines. Yet, virus-specific CD8 T cells often persist for long periods of time during chronic infections. We have addressed this apparent paradox by examining the mechanism for maintaining virus-specific CD8 T cells during chronic infection. We find that homeostatic cytokines (e.g., IL-7/15), inflammatory signals, and priming of recent thymic emigrants are not sufficient to maintain virus-specific CD8 T cells over time during chronic infection. Rather, our results demonstrate that viral peptide is required for virus-specific CD8 T cell persistence during chronic infection. Moreover, this viral antigen-dependent maintenance results in a dramatically different type of T cell division than is normally observed during memory T cell homeostasis. Rather than undergoing slow, steady homeostatic turnover during chronic viral infection, CD8 T cells undergo extensive peptide-dependent division, yet cell numbers remain relatively stable. These results indicate that antigen-specific CD8 T cell responses during persisting infection are maintained by a mechanism distinct from that after acute infection.


Automated surveillance to detect postprocedure safety signals of approved cardiovascular devices.
Ensuring the safety of medical devices challenges current surveillance approaches, which rely heavily on voluntary reporting of adverse events. Automated surveillance of clinical registries may provide early warnings in the postmarket evaluation of medical device safety. To determine whether automated safety surveillance of clinical registries using a computerized tool can provide early warnings regarding the safety of new cardiovascular devices. Prospective propensity-matched cohort analysis of 7 newly introduced cardiovascular devices, using clinical data captured in the Massachusetts implementation of the National Cardiovascular Data Repository CathPCI Registry for all adult patients undergoing percutaneous coronary intervention from April 2003 through September 2007 in Massachusetts. Presence of any safety alert, triggered if the cumulative observed risk for a given device exceeded the upper 95% confidence interval (CI) of comparator control device. Predefined sensitivity analyses assessed robustness of alerts when triggered. We evaluated 74,427 consecutive interventional coronary procedures. Three of 21 safety analyses triggered sustained alerts in 2 implantable devices. Patients receiving Taxus Express2 drug-eluting stents experienced a 1.28-fold increased risk of postprocedural myocardial infarction (2.87% vs 2.25%; absolute risk increase, 0.62% [95% CI, 0.25%-0.99%]) and a 1.21-fold increased risk of major adverse cardiac events (4.24% vs 3.50%; absolute increase, 0.74% [95% CI, 0.29%-1.19%]) compared with those receiving alternative drug-eluting stents. Patients receiving Angio-Seal STS vascular closure devices experienced a 1.51-fold increased risk of major vascular complications (1.09% vs 0.72%; absolute increased risk, 0.37% [95% CI, 0.03%-0.71%]) compared with those receiving alternative vascular closure devices. Sensitivity analyses confirmed increased risk following use of the Taxus Express2 stent but not the Angio-Seal STS device. Automated prospective surveillance of clinical registries is feasible and can identify low-frequency safety signals for new cardiovascular devices.


High-energy, kHz, picosecond hybrid Yb-doped chirped-pulse amplifier.
We report on a diode-pumped, hybrid Yb-doped chirped-pulse amplification (CPA) laser system with a compact pulse stretcher and compressor, consisting of Yb-doped fiber preamplifiers, a room-temperature Yb:KYW regenerative amplifier (RGA), and cryogenic Yb:YAG multi-pass amplifiers. The RGA provides a relatively broad amplification bandwidth and thereby a long pulse duration to mitigate B-integral in the CPA chain. The ~1030-nm laser pulses are amplified up to 70 mJ at 1-kHz repetition rate, currently limited by available optics apertures, and then compressed to ~6 ps with high efficiency. The near-diffraction-limited beam focusing quality is demonstrated with M(x)(2) = 1.1 and M(y)(2) = 1.2. The shot-to-shot energy fluctuation is as low as ~1% (rms), and the long-term energy drift and beam pointing stability for over 8 hours measurement are ~3.5% and <6 μrad (rms), respectively. To the best of our knowledge, this hybrid laser system produces the most energetic picosecond pulses at kHz repetition rates among rod-type laser amplifiers. With an optically synchronized Ti:sapphire seed laser, it provides a versatile platform optimized for pumping optical parametric chirped-pulse amplification systems as well as driving inverse Compton scattered X-rays.


Adult Functional Outcomes of Common Childhood Psychiatric Problems: A Prospective, Longitudinal Study.
Psychiatric problems are among the most common health problems of childhood. To test whether these health problems adversely affect adult functioning even if the problems themselves do not persist. Prospective, population-based study of 1420 participants from 11 predominantly rural counties of North Carolina who were assessed with structured interviews up to 6 times during childhood (9-16 years of age, for a total 6674 observations) for common psychiatric diagnoses and subthreshold psychiatric problems. The period for this study was from 1993 to 2010. A total of 1273 participants were assessed 3 times during young adulthood (19, 21, and 24-26 years of age, for a total of 3215 observations) for adverse outcomes related to health, the legal system, personal finances, and social functioning. Participants with a childhood disorder had 6 times higher odds (odds ratio [OR], 5.9 [95% CI, 3.6-9.7]) of at least 1 adverse adult outcome (ie, indicator) compared with those with no history of psychiatric problems and 9 times higher odds (OR, 8.7 [95% CI, 4.3-17.8]) of 2 or more such indicators (1 indicator: 59.5% vs 19.9% [P < .001]; ≥ 2 indicators: 34.2% vs 5.6% [P < .001]). These associations persisted after statistically controlling for childhood psychosocial hardships and adult psychiatric problems. Risk was not limited to those who received a diagnosis; participants with subthreshold psychiatric problems had 3 times higher odds (OR, 2.9 [95% CI, 1.8-4.8]) of adult adverse outcomes and 5 times higher odds (OR, 5.1 [95% CI, 2.4-10.7]) of 2 or more outcomes (1 indicator: 41.9% vs 19.9% [P < .001]; ≥ 2 indicators: 23.2% vs 5.6% [P < .001]). The best diagnostic predictor of adverse outcomes was cumulative childhood exposure to psychiatric disorders. Common, typically moderately impairing, childhood psychiatric problems are associated with a disrupted transition to adulthood even if the problems do not persist into adulthood and even if the problems are subthreshold. Such problems provide a potential target for public health efforts to ameliorate adult suffering and morbidity.


Field Performance Assessment of Irradiated Aedes albopictus Males Through Mark-Release-Recapture Trials With Multiple Release Points.
Mark-release-recapture (MRR) trials have been conducted in Northern Italy to evaluate the capacity of radio-substerilized Aedes albopictus males to survive, disperse, and engage in mating in the field. Two MRR sessions with the human landing collection method (HLC) were conducted with the simultaneous release of irradiated males marked with four different pigment colors. The survival and dispersal rates seem to be influenced more by environmental factors such as barriers, shading, and vegetation rather than weather parameters. In this study, we confirmed a positive linear relationship between the sterile adult male's daily survival rate and the relative humidity previously reported in similar experimental conditions and a different dispersal capacity of the released A. albopictus males in low- (NDVI index <0.4) and high (NDVI index >0.4)-vegetated areas. Consistent with previous studies, A. albopictus males have their maximal dispersion in the first days after release, while in the following days the males become more stationary. The similar field performances obtained with marked and unmarked radio-sterilized and untreated A. albopictus males on similar environments confirm the negligible effects of irradiation and marking procedures on the quality of the males released. The similar sterile to wild (S/W) male ratio measured in high- and low-vegetation areas in the release sites indicates a similar distribution pattern for the wild and the released sterile males. According to the MRR data collected, the Lincoln index estimated different A. albopictus mean population densities in the study areas equal to 7,000 and 3,000 male/ha, respectively.


Arhgef1 is required by T cells for the development of airway hyperreactivity and inflammation.
Arhgef1 is an intracellular protein, expressed by hematopoietic cells, that regulates signaling by both G protein-coupled receptors and RhoA, and, consequently, is required for appropriate migration and adhesion of diverse leukocyte populations. To evaluate a possible contribution for Arhgef1 in the development of airway inflammation and airway hyperreactivity. Arhgef1-deficient (Arhgef1-/-) and wild-type (WT) mice were sensitized and airway challenged, followed by measurement of airway responsiveness to inhaled methacholine. Inflammation was assessed by several parameters that included flow cytometric analysis and histology. Arhgef1-deficient recipients were reconstituted with WT T lymphocytes before sensitization and challenge, and again measured for airway responsiveness and inflammation. Cytokine production in response to specific antigen was measured in cultures of isolated leukocytes from lung and spleen and compared with the levels generated in lung and spleen explant cultures. Arhgef1-/- mice display significantly reduced airway hyperreactivity, Th2 cytokine production, and lung inflammation, despite intact systemic immunity. After airway challenge of Arhgef1-/- mice, antigen-specific T cells were present in mutant lungs, but were found to interact with CD11c+ cells at a significantly reduced frequency. Adoptive transfer of WT T cells into Arhgef1-/- mice restored airway hyperreactivity and inflammation. These data demonstrate that T cells depend on Arhgef1 to promote lung inflammation. Moreover, a deficiency in Arhgef1 results in reduced T cell-CD11c+ antigen-presenting cell interaction, and likely underscores the inability of Arhgef1-/- mice to mount an adaptive immune response to airway challenge.


Identification of morphological differences between avian influenza A viruses grown in chicken and duck cells.
Although wild ducks are considered to be the major reservoirs for most influenza A virus subtypes, they are typically resistant to the effects of the infection. In contrast, certain influenza viruses may be highly pathogenic in other avian hosts such as chickens and turkeys, causing severe illness and death. Following in vitro infection of chicken and duck embryo fibroblasts (CEF and DEF) with low pathogenic avian influenza (LPAI) viruses, duck cells die more rapidly and produce fewer infectious virions than chicken cells. In the current study, the morphology of viruses produced from CEF and DEF cells infected with low pathogenic avian H2N3 was examined. Transmission electron microscopy showed that viruses budding from duck cells were elongated, while chicken cells produced mostly spherical virions; similar differences were observed in viral supernatants. Sequencing of the influenza genome of chicken- and duck-derived H2N3 LPAI revealed no differences, implicating host cell determinants as responsible for differences in virus morphology. Both DEF and CEF cells produced filamentous virions of equine H3N8 (where virus morphology is determined by the matrix gene). DEF cells produced filamentous or short filament virions of equine H3N8 and avian H2N3, respectively, even after actin disruption with cytochalasin D. These findings suggest that cellular factors other than actin are responsible for the formation of filamentous virions in DEF cells. The formation of elongated virions in duck cells may account for the reduced number of infectious virions produced and could have implications for virus transmission or maintenance in the reservoir host.


Screening for Excessive Alcohol Use and Brief Counseling of Adults - 17 States and the District of Columbia, 2014.
Excessive and/or risky alcohol use* resulted in $249 billion in economic costs in 2010 (1) and >88,000 deaths in the United States every year from 2006 to 2010 (2). It is associated with birth defects and disabilities (e.g., fetal alcohol spectrum disorders [FASDs]), increases in chronic diseases (e.g., heart disease and breast cancer), and injuries and violence (e.g., motor vehicle crashes, suicide, and homicide).† Since 2004, the U.S. Preventive Services Task Force (USPSTF) has recommended alcohol misuse screening and brief counseling (also known as alcohol screening and brief intervention or ASBI) for adults aged ≥18 years (3).§ Among adults, ASBI reduces episodes of binge-level consumption, reduces weekly alcohol consumption, and increases compliance with recommended drinking limits in those who have an intervention in comparison to those who do not (3). A recent study suggested that health care providers rarely talk with patients about alcohol use (4). To estimate the prevalence of U.S. adults who reported receiving elements of ASBI, CDC analyzed 2014 Behavioral Risk Factor Surveillance System (BRFSS) data from 17 states¶ and the District of Columbia (DC). Weighted crude and age-standardized overall and state-level prevalence estimates were calculated by selected drinking patterns and demographic characteristics. Overall, 77.7% of adults (age-standardized estimate) reported being asked about alcohol use by a health professional in person or on a form during a checkup, but only 32.9% reported being asked about binge-level alcohol consumption (3). Among binge drinkers, only 37.2% reported being asked about alcohol use and advised about the harms of drinking too much, and only 18.1% reported being asked about alcohol use and advised to reduce or quit drinking. Widespread implementation of ASBI and other evidence-based interventions could help reduce excessive alcohol use in adults and related harms.


Immunotoxicological effects of JP-8 jet fuel exposure.
Chronic exposure to jet fuel has been shown to have adverse effects on human liver function, to cause emotional dysfunction, to cause abnormal electroencephalograms, to cause shortened attention spans, and to decrease sensorimotor speed (3-5). Due to the decision by the United States Air Force to implement the widespread use of JP-8 jet fuel in its operations, a thorough understanding of its potential effects upon exposed personnel is both critical and necessary. Exposure to potential environmental toxicants such as JP-8 may have significant effects on host systems beyond those readily visible (e.g., physiology, cardiology, respiratory, etc.); e.g., the immune system. Significant changes in immune consequences, even if short-lived, may have serious consequences for the exposed host that may impinge affect susceptibility to infectious agents. Major alterations in immune function that are long-lasting may result in an increased likelihood of development and/or progression of cancer, as well as autoimmune diseases. In the current study mice were exposed for 1h/day for 7 days to varying concentrations of aerosolized JP-8 jet fuel to simulate occupational exposures. Twenty-four hours after the last exposure the mice were analyzed for effects on their immune systems. It was observed that even at exposure concentrations as low as 100 mg/m3 detrimental effects on the immune system occurred. Decreases in viable immune cell numbers and immune organ weights were found. Jet fuel exposure resulted in losses of different immune cell subpopulations depending upon the immune organ being examined. Further, JP-8 exposure resulted in significantly decreased immune function, as analyzed by mitogenesis assays. Suppressed immune function could not be overcome by the addition of exogenous growth factors known to stimulate immune function. Thus, short-term, low concentration exposure of mice to JP-8 jet fuel caused significant toxicological effects on the immune system. It appears that the immune system may be the most sensitive indicator of toxicological damage due to JP-8 exposure, as effects were seen at concentrations of jet fuel that did not evidence change in other biological systems. Such changes may have significant effects on the health of the exposed individual.


Targeted Next Generation Sequencing for malaria research in Africa: current status and outlook.
Targeted Next Generation Sequencing (TNGS) is an efficient and economical Next Generation Sequencing (NGS) platform and the preferred choice when specific genomic regions are of interest. So far, only institutions located in middle and high-income countries have developed and implemented the technology, however, the efficiency and cost savings, as opposed to more traditional sequencing methodologies (e.g. Sanger sequencing) make the approach potentially well suited for resource-constrained regions as well. In April 2018, scientists from the Plasmodium Diversity Network Africa (PDNA) and collaborators met during the 7th Pan African Multilateral Initiative of Malaria (MIM) conference held in Dakar, Senegal to explore the feasibility of applying TNGS to genetic studies and malaria surveillance in Africa. The group of scientists reviewed the current experience with TNGS platforms in sub-Saharan Africa (SSA) and identified potential roles the technology might play to accelerate malaria research, scientific discoveries and improved public health in SSA. Research funding, infrastructure and human resources were highlighted as challenges that will have to be mitigated to enable African scientists to drive the implementation of TNGS in SSA. Current roles of important stakeholders and strategies to strengthen existing networks to effectively harness this powerful technology for malaria research of public health importance were discussed.


Bioavailability of iron, zinc, and other trace minerals from vegetarian diets.
Iron and zinc are currently the trace minerals of greatest concern when considering the nutritional value of vegetarian diets. With elimination of meat and increased intake of phytate-containing legumes and whole grains, the absorption of both iron and zinc is lower with vegetarian than with nonvegetarian, diets. The health consequences of lower iron and zinc bioavailability are not clear, especially in industrialized countries with abundant, varied food supplies, where nutrition and health research has generally supported recommendations to reduce meat and increase legume and whole-grain consumption. Although it is clear that vegetarians have lower iron stores, adverse health effects from lower iron and zinc absorption have not been demonstrated with varied vegetarian diets in developed countries, and moderately lower iron stores have even been hypothesized to reduce the risk of chronic diseases. Premenopausal women cannot easily achieve recommended iron intakes, as modified for vegetarians, with foods alone; however, the benefit of routine iron supplementation has not been demonstrated. It may be prudent to monitor the hemoglobin of vegetarian children and women of childbearing age. Improved assessment methods are required to determine whether vegetarians are at risk of zinc deficiency. In contrast with iron and zinc, elements such as copper appear to be adequately provided by vegetarian diets. Although the iron and zinc deficiencies commonly associated with plant-based diets in impoverished nations are not associated with vegetarian diets in wealthier countries, these nutrients warrant attention as nutritional assessment methods become more sensitive and plant-based diets receive greater emphasis.


Diet and energy-sensing inputs affect TorC1-mediated axon misrouting but not TorC2-directed synapse growth in a Drosophila model of tuberous sclerosis.
The Target of Rapamycin (TOR) growth regulatory system is influenced by a number of different inputs, including growth factor signaling, nutrient availability, and cellular energy levels. While the effects of TOR on cell and organismal growth have been well characterized, this pathway also has profound effects on neural development and behavior. Hyperactivation of the TOR pathway by mutations in the upstream TOR inhibitors TSC1 (tuberous sclerosis complex 1) or TSC2 promotes benign tumors and neurological and behavioral deficits, a syndrome known as tuberous sclerosis (TS). In Drosophila, neuron-specific overexpression of Rheb, the direct downstream target inhibited by Tsc1/Tsc2, produced significant synapse overgrowth, axon misrouting, and phototaxis deficits. To understand how misregulation of Tor signaling affects neural and behavioral development, we examined the influence of growth factor, nutrient, and energy sensing inputs on these neurodevelopmental phenotypes. Neural expression of Pi3K, a principal mediator of growth factor inputs to Tor, caused synapse overgrowth similar to Rheb, but did not disrupt axon guidance or phototaxis. Dietary restriction rescued Rheb-mediated behavioral and axon guidance deficits, as did overexpression of AMPK, a component of the cellular energy sensing pathway, but neither was able to rescue synapse overgrowth. While axon guidance and behavioral phenotypes were affected by altering the function of a Tor complex 1 (TorC1) component, Raptor, or a TORC1 downstream element (S6k), synapse overgrowth was only suppressed by reducing the function of Tor complex 2 (TorC2) components (Rictor, Sin1). These findings demonstrate that different inputs to Tor signaling have distinct activities in nervous system development, and that Tor provides an important connection between nutrient-energy sensing systems and patterning of the nervous system.


Automatic Sleep Monitoring Using Ear-EEG.
The monitoring of sleep patterns without patient's inconvenience or involvement of a medical specialist is a clinical question of significant importance. To this end, we propose an automatic sleep stage monitoring system based on an affordable, unobtrusive, discreet, and long-term wearable in-ear sensor for recording the electroencephalogram (ear-EEG). The selected features for sleep pattern classification from a single ear-EEG channel include the spectral edge frequency and multi-scale fuzzy entropy, a structural complexity feature. In this preliminary study, the manually scored hypnograms from simultaneous scalp-EEG and ear-EEG recordings of four subjects are used as labels for two analysis scenarios: 1) classification of ear-EEG hypnogram labels from ear-EEG recordings; and 2) prediction of scalp-EEG hypnogram labels from ear-EEG recordings. We consider both 2-class and 4-class sleep scoring, with the achieved accuracies ranging from 78.5% to 95.2% for ear-EEG labels predicted from ear-EEG, and 76.8% to 91.8% for scalp-EEG labels predicted from ear-EEG. The corresponding Kappa coefficients range from 0.64 to 0.83 for Scenario 1, and indicate substantial to almost perfect agreement, while for Scenario 2 the range of 0.65-0.80 indicates substantial agreement, thus further supporting the feasibility of in-ear sensing for sleep monitoring in the community.


An investigation of risk factors for renal cell carcinoma by histologic subtype in two case-control studies.
To investigate whether renal cell carcinoma (RCC) histologic subtypes possess different etiologies, we conducted analyses of established RCC risk factors by subtype (clear cell, papillary and chromophobe) in two case-control studies conducted in the United States (1,217 cases, 1,235 controls) and Europe (1,097 cases, 1,476 controls). Histology was ascertained for 706 U.S. cases (58% of total) and 917 European cases (84%) through a central slide review conducted by a single pathologist. For the remaining cases, histology was abstracted from the original diagnostic pathology report. Case-only analyses were performed to compute odds ratios (ORs) and 95% confidence intervals (CI) summarizing subtype differences by age, sex and race. Case-control analyses were performed to compute subtype-specific ORs for other risk factors using polytomous regression. In case-only analyses, papillary cases (N = 237) were older (OR = 1.2, 95% CI = 1.1-1.4 per 10-year increase), less likely to be female (OR = 0.5, 95% CI = 0.4-0.8) and more likely to be black (OR = 2.6, 95% CI = 1.8-3.9) as compared to clear cell cases (N = 1,524). In case-control analyses, BMI was associated with clear cell (OR = 1.2, 95% CI = 1.1-1.3 per 5 kg/m(2) increase) and chromophobe RCC (N = 80; OR = 1.2, 95% CI = 1.1-1.4), but not papillary RCC (OR = 1.1, 95% CI = 1.0-1.2; test versus clear cell, p = 0.006). No subtype differences were observed for associations with smoking, hypertension or family history of kidney cancer. Our findings support the existence of distinct age, sex and racial distributions for RCC subtypes, and suggest that the obesity-RCC association differs by histology.


Challenges and opportunities in designing clinical trials for neuromyelitis optica.
Current management of neuromyelitis optica (NMO) is noncurative and only partially effective. Immunosuppressive or immunomodulatory agents are the mainstays of maintenance treatment. Safer, better-tolerated, and proven effective treatments are needed. The perceived rarity of NMO has impeded clinical trials for this disease. However, a diagnostic biomarker and recognition of a wider spectrum of NMO presentations has expanded the patient population from which study candidates might be recruited. Emerging insights into the pathogenesis of NMO have provided rationale for exploring new therapeutic targets. Academic, pharmaceutical, and regulatory communities are increasingly interested in meeting the unmet needs of patients with NMO. Clinical trials powered to yield unambiguous outcomes and designed to facilitate rapid evaluation of an expanding pipeline of experimental agents are needed. NMO-related disability occurs incrementally as a result of attacks; thus, limiting attack frequency and severity are critical treatment goals. Yet, the severity of NMO and perception that currently available agents are effective pose challenges to study design. We propose strategies for NMO clinical trials to evaluate agents targeting recovery from acute attacks and prevention of relapses, the 2 primary goals of NMO treatment. Aligning the interests of all stakeholders is an essential step to this end.


Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia.
Although angiogenesis is a prerequisite for the growth of most human solid tumours, alternative mechanisms of vascularisation can be adopted. We have previously described a non-angiogenic growth pattern in liver metastases of colorectal adenocarcinomas (CRC) in which tumour cells replace hepatocytes at the tumour-liver interface, preserving the liver architecture and co-opting the sinusoidal blood vessels. The aim of this study was to determine whether this replacement pattern occurs during liver metastasis of breast adenocarcinomas (BC) and whether the lack of an angiogenic switch in such metastases is due to the absence of hypoxia and subsequent vascular fibrinogen leakage. The growth pattern of 45 BC liver metastases and 28 CRC liver metastases (73 consecutive patients) was assessed on haematoxylin- and eosin-stained tissue sections. The majority of the BC liver metastases had a replacement growth pattern (96%), in contrast to only 32% of the CRC metastases (P<0.0001). The median carbonic anhydrase 9 (CA9) expression (M75 antibody), as a marker of hypoxia, (intensity x % of stained tumour cells) was 0 in the BC metastases and 53 in the CRC metastases (P<0.0001). There was CA9 expression at the tumour-liver interface in only 16% of the BC liver metastases vs 54% of the CRC metastases (P=0.002). There was fibrin (T2G1 antibody) at the tumour-liver interface in only 21% of the BC metastases vs 56% of the CRC metastases (P=0.04). The median macrophage count (Chalkley morphometry; KP-1 anti-CD68 antibody) at the interface was 4.3 and 7.5, respectively (P<0.0001). Carbonic anhydrase 9 score and macrophage count were positively correlated (r=0.42; P=0.002) in all metastases. Glandular differentiation was less in the BC liver metastases: 80% had less than 10% gland formation vs only 7% of the CRC metastases (P<0.0001). The liver is a densely vascularised organ and can host metastases that exploit this environment by replacing the hepatocytes and co-opting the vasculature. Our findings confirm that a non-angiogenic pattern of liver metastasis indeed occurs in BC, that this pattern of replacement growth is even more prevalent than in CRC, and that the process induces neither hypoxia nor vascular leakage.


Total colonic aganglionosis and Hirschsprung's disease: shades of the same or different?
Total colonic aganglionosis is a relatively uncommon form of Hirschsprung's disease (HSCR) occurring in approximately 2-13% of cases. It can probably be divided into total colonic aganglionosis (TCA; defined as aganglionosis extending from the anus to at least the ileocaecal valve, but no more than 50 cm proximal to the ileocaecal valve) and total colonic and small bowel aganglionosis, which may involve a very long segment of aganglionosis. Clinically, they appear to represent a different spectrum of disease in terms of presentation and difficulties in diagnosis which may be experienced, suggesting a different pathophysiology from the more common forms of HSCR. It is not yet clear whether TCA merely represents a long form of HSCR or a different expression of the disease. There are a number of differences between TCA and other forms of HSCR, which require an explanation if its ubiquitous clinical features are to be understood. There is some evidence suggesting that instead of being purely congenital, it may represent certain different pathophysiologic mechanisms, some of which may continue to be active after birth. This study reviews all that is known about the clinical, radiological and histopathologic differences between TCA and the more frequently encountered recto-sigmoid (or short-segment) and correlates them with what is currently known about the genetic and molecular biologic background to find possible pathogenetic mechanisms.


Breathlessness in a virtual world: An experimental paradigm testing how discrepancy between VR visual gradients and pedal resistance during stationary cycling affects breathlessness perception.
The sensation of breathlessness is often attributed to perturbations in cardio-pulmonary physiology, leading to changes in afferent signals. New evidence suggests that these signals are interpreted in the light of prior "expectations". A misalignment between afferent signals and expectations may underly unexplained breathlessness. Using a novel immersive virtual reality (VR) exercise paradigm, we investigated whether manipulating an individual's expectation of effort (determined by a virtual hill gradient) may alter their perception of breathlessness, independent from actual effort (the physical effort of cycling). Nineteen healthy volunteers completed a single experimental session where they exercised on a cycle ergometer while wearing a VR headset. We created an immersive virtual cycle ride where participants climbed up 100 m hills with virtual gradients of 4%, 6%, 8%, 10% and 12%. Each virtual hill gradient was completed twice: once with a 4% cycling ergometer resistance and once with a 6% resistance, allowing us to dissociate expected effort (virtual hill gradient) from actual effort (power). At the end of each hill, participants reported their perceived breathlessness. Linear mixed effects models were used to examine the independent contribution of actual effort and expected effort to ratings of breathlessness (0-10 scale). Expectation of effort (effect estimate ± std. error, 0.63 ± 0.11, P < 0.001) and actual effort (0.81 ± 0.21, P < 0.001) independently explained subjective ratings of breathlessness, with comparable contributions of 19% and 18%, respectively. Additionally, we found that effort expectation accounted for 6% of participants' power and was a significant, independent predictor (0.09 ± 0.03; P = 0.001). An individuals' expectation of effort is equally important for forming perceptions of breathlessness as the actual effort required to cycle. A new VR paradigm enables this to be experimentally studied and could be used to re-align breathlessness and enhance training programmes.


Cat's claw: an Amazonian vine decreases inflammation in osteoarthritis.
Cat's claw (Uncaria tomentosa and Uncaria guianesis) is a medicinal plant from the Amazon commonly used to treat disorders such as arthritis, gastritis and osteoarthritis. The mechanism of cat's claw appears to be as an inhibitor of TNFalpha and antioxidant. Understanding the processes in osteoarthritis may facilitate and clarify the potential role of cat's claw as a complementary therapy to assist in the reduction of pro-inflammatory mediators and effectors. The clinical relevance of this therapy as a viable modality of intervention will be discussed.


Multiple sclerosis and organic solvents.
We investigated a possible causal relation between exposure to organic solvents in Danish workers (housepainters, typographers/printers, carpenters/cabinetmakers) and onset of multiple sclerosis. Data on men included in the Danish Multiple Sclerosis Register (3,241 men) were linked with data from the 1970 census from the National Bureau of Statistics in Denmark, which has data on occupational status for 1,768,846 men between 15 and 74 years of age. From this census, we ascertained a group of 124,766 "solvent-exposed" men and an "unexposed" group of 87,501 male electricians, bricklayers, and butchers. Over a follow-up period of 20 years, we observed no increase in the incidence of multiple sclerosis among men presumed to be exposed to organic solvents. It was not possible to obtain data on potential confounders, and the study design has some potential for selection bias. Nevertheless, the study does not support existing hypotheses regarding an association between occupational exposure to organic solvents and multiple sclerosis.


Feasibility of interstitial CT lymphography using optimized iodized oil emulsion in rats.
To formulate an iodine-based contrast agent with an oil-in-water emulsion and to evaluate the feasibility of the agent for use as an interstitial computed tomographic (CT) lymphographic agent in a normal rat model. The effect of iodized oil (lipiodol) content and the type of surfactant/cosurfactant on the resultant emulsion size and polydispersity was investigated to obtain an optimized lipiodol emulsion for CT lymphography. Optimized emulsions (144 mg/mL) were injected in the hind paws of 6 rats, using 0.5 mL per paw. As control groups, iopamidol solution and lipiodol diluted with squalene to adjust the injection volume with iodine concentration equivalent to the emulsions were used. Precontrast and postcontrast CT images up to 1 week after contrast agent injection were obtained. Time-enhancement curves of the popliteal lymph nodes were obtained. Analysis of variance and post hoc analysis with the Dunn procedure were used for comparing mean peak enhancement, time to peak enhancement, and sustained duration of contrast enhancement. Optimized emulsion formulations composed of 30% lipiodol and 282 mg/mL of 9:1 surfactant mixture (Tween 80:TPGS [alpha-tocopheryl polyethylene glycol succinate], Tween 80:Kollidon 12 PF, or Tween 80:Span 85) exhibited mean particle size less than 120 nm, and they were stable without significant particle size change up to 1 month. Targeted lymph nodes in all emulsion groups showed continuously increasing enhancement until 4 or 8 hours after injection, followed by continuous washout. Peak enhancement (time to peak enhancement) was 172.4 +/- 54.5 HU (Hounsfield unit) (384.0 +/- 131.5 minutes) for Tween 80:TPGS; 172.8 +/- 28.0 HU (432.0 +/- 107.3 minutes) for Tween 80:Kollidon 12 PF, and 177.2 +/- 68.9 HU (294.0 +/- 190.2 minutes) for Tween 80:Span 85. For iopamidol, peak enhancement of 153.0 +/- 46.1 HU (0.5 +/- 0.5 minutes) occurred early with rapid washout. For lipiodol as a reference agent, contrast enhancement continuously increased even 1 week after injection without washout (peak enhancement, 486.0 +/- 97.4 HU). Peak enhancement among the emulsion groups and the iopamidol group was not statistically different (P = 0.95). All emulsion groups showed more prolonged enhancement than the iopamidol group; enhancement duration for the emulsion groups was 534.0 +/- 481.1 minutes for Tween 80:TPGS; 957.0 +/- 524.8 minutes for Tween 80:Kollidon 12 PF; and 750.0 +/- 566.0 minutes for Tween 80:Span 85, and enhancement duration for iopamidol was 8.2 +/- 12.3 minutes (all P < 0.05 in multiple comparisons). However, there was no significant difference in enhancement duration among the 3 emulsion groups (P > 0.05). Iodized oil emulsion made with a surfactant mixture (Tween 80 as the main surfactant and TPGS, Kollidon 12 PF, or Span 85 as the cosurfactant) provided sufficient and sustained contrast enhancement on CT of targeted lymph nodes with washout on delayed phase.


Editors' Review and Introduction: The Cultural Evolution of Cognition.
This topic addresses a question of key interest to cognitive science, namely which factors may have triggered, constrained, or shaped the course of cognitive evolution. It highlights the relevance of culture as a driving force in this process, with a special focus on social learning and language, conceptual tools, and material culture. In so doing, the topic combines two goals: to provide an overview of current empirical and theoretical work leading this field, tailored for a wider cognitive science audience, and to investigate the potential for integrating multiple perspectives across several timescales and levels of analysis, from the microlevel of individual behavior to the macrolevel of cultural change and language diversification. One key purpose is to assess the extent to which the different research approaches can cross-fertilize each other, thereby also contributing to the advancement of cognitive science more broadly.


Changes in muscle size and architecture following 20 days of bed rest.
Five healthy men carried out a program of head-down bed rest (BR) for 20 days. Before and after BR, a series of cross-sectional scans of the thigh were performed using magnetic resonance imaging, from which volumes of the quadriceps muscles were determined and physiological cross-sectional areas (PCSA) were calculated. Muscle thickness and pennation angles of the triceps brachii, vastus lateralis, and triceps surae muscles were also determined by ultrasonography. During BR, subjects performed unilateral isokinetic knee extension exercises every day. The contralateral limb served as a control. Decrease in PCSA after BR was greater in the control (-10.2 +/- 6.3%) than in the trained limb (-5.2 +/- 4.2%). Among the quadriceps, vastus intermedius in the control limb was predominantly atrophied by BR with respect to the volume and PCSA, and the rectus femoris showed the greatest training effect and retained its size in the trained limb. Decreases in muscle thicknesses in leg muscles were not prevented by the present exercise protocol, suggesting a need for specific exercise training for these muscles. Neither trained nor control muscles showed significant changes in pennation angles in any muscles after BR, suggesting that muscle architecture does not change remarkably by muscle atrophy by up to 10%.


Stressful intensive care unit medical crises: How individual responses impact on team performance.
Intensive care units (ICUs) are recognized as stressful environments. However, the conditions in which stressors may affect health professionals' performance and well-being and the conditions that potentially lead to impaired performance and staff psychological distress are not well understood. The purpose of this study was to determine healthcare professionals' perceptions regarding the factors that lead to stress responses and performance impairments during ICU medical crises. A qualitative study in a university-affiliated ICU in Canada. We conducted 32 individual semistructured interviews of ICU nurses, staff physicians, residents, and respiratory therapists in a university-affiliated hospital. The transcripts of the audiotaped interviews were analyzed using an inductive thematic methodology. Increased workload, high stakes, and heavy weight of responsibility were recognized as common stressors during ICU crises. However, a high level of individual and team resources available to face such demands was also reported. When the patient's condition was changing or deteriorating unpredictably or when the expected resources were unavailable, crises were assessed by some team members as threatening, leading to individual distress. Once manifested, this emotional distress was strongly contagious to other team members. The ensuing collective anxiety was perceived as disruptive for teamwork and deleterious for individual and collective performance. Individual distress reactions to ICU crises occurred in the presence of unexpectedly high demands unmatched by appropriate resources and were contagious among other team members. Given the high uncertainty surrounding many ICU medical crises, strategies aimed at preventing distress contagion among ICU health professionals may improve team performance and individual well-being.


The rice narrow leaf2 and narrow leaf3 loci encode WUSCHEL-related homeobox 3A (OsWOX3A) and function in leaf, spikelet, tiller and lateral root development.
· In order to understand the molecular genetic mechanisms of rice (Oryza sativa) organ development, we studied the narrow leaf2 narrow leaf3 (nal2 nal3; hereafter nal2/3) double mutant, which produces narrow-curly leaves, more tillers, fewer lateral roots, opened spikelets and narrow-thin grains. · We found that narrow-curly leaves resulted mainly from reduced lateral-axis outgrowth with fewer longitudinal veins and more, larger bulliform cells. Opened spikelets, possibly caused by marginal deformity in the lemma, gave rise to narrow-thin grains. · Map-based cloning revealed that NAL2 and NAL3 are paralogs that encode an identical OsWOX3A (OsNS) transcriptional activator, homologous to NARROW SHEATH1 (NS1) and NS2 in maize and PRESSED FLOWER in Arabidopsis. · OsWOX3A is expressed in the vascular tissues of various organs, where nal2/3 mutant phenotypes were displayed. Expression levels of several leaf development-associated genes were altered in nal2/3, and auxin transport-related genes were significantly changed, leading to pin mutant-like phenotypes such as more tillers and fewer lateral roots. OsWOX3A is involved in organ development in rice, lateral-axis outgrowth and vascular patterning in leaves, lemma and palea morphogenesis in spikelets, and development of tillers and lateral roots.


A cluster of carboxylic groups in PsbO protein is involved in proton transfer from the water oxidizing complex of Photosystem II.
The hypothesis presented here for proton transfer away from the water oxidation complex of Photosystem II (PSII) is supported by biochemical experiments on the isolated PsbO protein in solution, theoretical analyses of better understood proton transfer systems like bacteriorhodopsin and cytochrome oxidase, and the recently published 3D structure of PS II (Pdb entry 1S5L). We propose that a cluster of conserved glutamic and aspartic acid residues in the PsbO protein acts as a buffering network providing efficient acceptors of protons derived from substrate water molecules. The charge delocalization of the cluster ensures readiness to promptly accept the protons liberated from substrate water. Therefore protons generated at the catalytic centre of PSII need not be released into the thylakoid lumen as generally thought. The cluster is the beginning of a localized, fast proton transfer conduit on the lumenal side of the thylakoid membrane. Proton-dependent conformational changes of PsbO may play a role in the regulation of both supply of substrate water to the water oxidizing complex and the resultant proton transfer.


Administration Rates of the Tdap Vaccine in Obstetric Patients.
Infants younger than 6 months of age are at high risk for contracting pertussis because of not being fully vaccinated. The Advisory Committee on Immunization Practices (ACIP) recommends vaccinating all pregnant women with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) between 27 and 36 weeks to offer passive immunity to the infant to help protect them until they are able to receive the full pertussis series. To assess and compare compliance with the 2013 ACIP recommendation of vaccinating pregnant women with Tdap at 27 to 36 weeks' gestation in 2 obstetric clinics. This cross-sectional, retrospective chart review evaluated Tdap vaccine compliance in a random sample of obstetric patients from October 2013 to September 2014. The primary outcome evaluated the proportion of patients who received Tdap between 27 and 36 weeks' gestation. Secondary outcomes included the proportion of patients who received Tdap at any point in pregnancy and within 30 days postpartum. The charts of 573 patients were reviewed, and 237 met inclusion criteria. For the primary outcome, 142 patients (59.9%) received the Tdap vaccine. Overall, 156 patients (65.8%) received Tdap at some point during the pregnancy. Factors associated with receiving the Tdap vaccination were insurance status, prenatal care risk level and site of prenatal care, receipt of the influenza vaccine, and preterm labor in the current pregnancy. The Tdap vaccine rate was 65.8%, with 59.9% of patients receiving the vaccine within the recommended ACIP timeframe. Further education, improvements in documentation, and chart reminders are needed to enhance administration.


A distinctive class of integron in the Vibrio cholerae genome.
The ability of bacteria to acquire and disseminate heterologous genes has been a major factor in the development of multiple drug resistance. A gene, intI4, was identified that encodes a previously unknown integrase that is associated with a "gene-VCR" organization (VCRs are Vibrio cholerae repeated sequences), similar to that of the well-characterized antibiotic resistance integrons. The similarity was confirmed by IntI1-mediated recombination of a gene-VCR cassette into a class 1 integron. VCR cassettes are found in a number of Vibrio species including a strain of V. metschnikovii isolated in 1888, suggesting that this mechanism of heterologous gene acquisition predated the antibiotic era.


Trends in poisoning hospitalization and mortality in Taiwan, 1999-2008: a retrospective analysis.
Subjects with non-fatal poisoning may be left with permanent, disabling sequelae, and the resultant long-term use of medical services smay be a burden on the public health care system. The objective of this study was to describe the epidemiology of poisoning in Taiwan from 1999 to 2008. We analyzed poisoning-related data of mortality rates sourced from official Taiwanese vital statistics and of hospitalization from the National Health Insurance (NHI) Research Database. The data were age-adjusted to the year 2000 Standard Population to determine 10-year hospitalization and mortality rate trends, which we stratified according to gender, age, and poisoning agent. Poisson regression was used to investigate the trends. There were 20,260 deaths and 210,021 hospitalizations related to poisoning, with mortality and hospitalization rates of 8.21 per 100,000 and 86.30 per 100,000 population, respectively. Males exhibited higher rates of mortality and hospitalization as a result of poisoning, with the highest risk in those aged 65 years or older. Medicinal drugs followed by pesticides were the two most common agents of poisoning. There was an increasing trend of both poisoning-related mortality and hospitalization rates during the study period, with a greater increase occurring in the hospitalization rate than in the mortality rate. We found the males aged 65 years or older were at highest risk of poisoning, with medicinal drugs being the leading cause. Hospitalization rates increased more than mortality rates over the 10-year period. Appropriate poisoning prevention programs need to be developed. We should strengthen case management and improve access to health services to increase survival in cases of poisoning.


Association of anhedonia with recurrent major adverse cardiac events and mortality 1 year after acute coronary syndrome.
Depression consistently predicts recurrent events and mortality in patients with acute coronary syndrome (ACS), but it has 2 core diagnostic criteria with distinct biological correlates-depressed mood and anhedonia (loss of pleasure or interest). To determine if depressed mood and/or anhedonia predict 1-year medical outcomes for patients with ACS. Observational cohort study of post-ACS patients hospitalized between May 2003 and June 2005. Within 1 week of admission, patients underwent a structured psychiatric interview assessing clinically impairing depressed mood, anhedonia, and major depressive episode (MDE). Also assessed were the Global Registry of Acute Coronary Events risk score, Charlson comorbidity index, left ventricular ejection fraction, antidepressant use, and depressive symptom severity using the Beck Depression Inventory. Cardiac units of 3 university hospitals in New York and Connecticut. Consecutive sample of 453 patients with ACS (age, 25-93 years; 42% women). All-cause mortality (ACM) and documented major adverse cardiac events (MACEs)-myocardial infarction, hospitalization for unstable angina, or urgent/emergency coronary revascularization)-actively surveyed for 1 year after admission. There were 67 events (16 deaths and 51 MACEs; 14.8%): 108 (24%) and 77 (17%) patients had anhedonia and depressed mood, respectively. Controlling for sex, age, and medical covariates, anhedonia (adjusted hazard ratio, 1.58; 95% confidence interval, 1.16-2.14; P < .01) was a significant predictor of combined MACE and ACM, but depressed mood was not. Anhedonia continued to significantly predict outcomes (P < .05) when additionally controlling for MDE diagnosis or depressive symptom severity. Findings were confirmed using depressed mood and anhedonia subscores from the Beck Depression Inventory in place of clinician interview ratings. Anhedonia identifies risk of MACE and ACM beyond that of established medical prognostic indicators, including MDE and depressive symptom severity. Correlates of anhedonia may add to the understanding of the link between depression and heart disease.


Reverse Shoulder Arthroplasty Augments for Glenoid Wear. Comparison of Posterior Augments to Superior Augments.
Patients who are candidates for a reverse total shoulder arthroplasty (rTSA) may have varying amounts and patterns of glenoid wear. The usual treatment of these deformities has been eccentric reaming or bone grafting. Eccentric reaming often removes a large amount of subchondral bone. Bone grafting is technically more difficult and introduces another mode of failure if the graft does not heal. The purpose of this study is to evaluate patients undergoing a rTSA with concomitant superior or posterior glenoid wear who were treated with a superior augmented baseplate (SAB) or posterior augmented baseplate (PAB) without eccentric reaming or bone grafting. Prospectively obtained data were queried from a multi-institutional IRB-approved database. Preoperative and postoperative data were analyzed from 39 patients who received a primary rTSA with either an 8° PAB or a 10° SAB and a minimum of 2 years follow-up. Twenty-four (10 females and 14 males, aged 72.3 ± 8.2 years) received a primary rTSA shoulder with a PAB. Fifteen patients (4 females and 11 males, aged 71.7 ± 9.2 years) received a primary rTSA shoulder with a SAB. Each patient was scored preoperatively and at latest follow-up using the SST, UCLA, ASES, Constant, and SPADI metrics. Active abduction, forward flexion, and active and passive external rotation with the arm at the side were also measured. The average follow-up for rTSA patients with a PAB was 25.6 ± 3.1 months, and the average follow-up for rTSA patients with a SAB was 32.5 ± 6.5 months. A Student's two-tailed, unpaired t-test was used to identify differences in preoperative and postoperative results, where p < 0.05 denoted a significant difference. All patients in both groups demonstrated significant improvements in pain and function following treatment with the reverse shoulder arthroplasty. The PAB rTSA cohort had a scapular notching rate of 6.3%, whereas the SAB rTSA cohort had a scapular notching rate of 14.3%. The PAB outperformed the SAB with the ASES, Constant, and active forward elevation measures. The PAB group outperformed the SAB group with the ASES and Constant outcome scores and forward flexion. The reason for this is unknown; however, it may be due to the posterior augment baseplate itself tensioning the remaining external rotators better than the superior augment, or it may be that the posterior augment group had a better posterior cuff. Both implant groups had no revisions or dislocations and had a low notching rate. It appears that a SAB for superior glenoid wear and a PAB for posterior glenoid wear are viable simple solutions in patients undergoing a rTSA, where each preserves glenoid bone and eliminates the need for glenoid bone grafting.


The frequently low cobalamin levels in dementia usually signify treatable metabolic, neurologic and electrophysiologic abnormalities.
Cobalamin levels are frequently low in patients with dementia, but it is unclear if they represent definable deficiency and what the mechanisms are. Therefore, patients being evaluated for dementia who had low cobalamin levels but no obvious evidence of deficiency were studied hematologically, neurologically and with metabolic tests and were re-evaluated after cobalamin treatment. Abnormalities suggestive of or diagnostic for deficiency were documented in most of the 16 demented and nondemented patients. Metabolic results: 50% of patients tested had abnormal deoxyuridine suppression and 44% had increased serum methylmalonic acid and/or homocysteine levels; these test results correlated with each other. Neurologic results: 73% of patients had clinical abnormalities, primarily mild neuropathies, not attributable to other causes, 75% had electroencephalographic abnormalities, 77% had abnormal visual evoked potentials and 33% had abnormal somatosensory potentials. Metabolic and neurologic dysfunction were present together or absent together in all but 2 cases. Cobalamin therapy improved 50-100% of the various types of abnormalities, although it did not improve cognitive function in the 13 demented patients. Food-cobalamin malabsorption was found in 60% of the patients. Despite the absence of megaloblastic anemia and rarity of traditional malabsorption of free cobalamin, low cobalamin levels in demented patients frequently represent mild cobalamin deficiency and are often associated with food-cobalamin malabsorption. Perhaps most importantly, this is accompanied not only by metabolic changes but by evidence of mild neurologic dysfunction. Their frequent reversibility by cobalamin confirms that these defects indeed arise from cobalamin deficiency. Although the long-standing dementia does not improve, treating such patients with cobalamin has other concrete benefits.


Inhibitors tethered near the acetylcholinesterase active site serve as molecular rulers of the peripheral and acylation sites.
The acetylcholinesterase (AChE) active site consists of a narrow gorge with two separate ligand binding sites: an acylation site (or A-site) at the bottom of the gorge where substrate hydrolysis occurs and a peripheral site (or P-site) at the gorge mouth. AChE is inactivated by organophosphates as they pass through the P-site and phosphorylate the catalytic serine in the A-site. One strategy to protect against organophosphate inactivation is to design cyclic ligands that will bind specifically to the P-site and block the passage of organophosphates but not acetylcholine. To accelerate the process of identifying cyclic compounds with high affinity for the AChE P-site, we introduced a cysteine residue near the rim of the P-site by site-specific mutagenesis to generate recombinant human H287C AChE. Compounds were synthesized with a highly reactive methanethiosulfonyl substituent and linked to this cysteine through a disulfide bond. The advantages of this tethering were demonstrated with H287C AChE modified with six compounds, consisting of cationic trialkylammonium, acridinium, and tacrine ligands with tethers of varying length. Modification by ligands with short tethers had little effect on catalytic properties, but longer tethering resulted in shifts in substrate hydrolysis profiles and reduced affinity for acridinium affinity resin. Molecular modeling calculations indicated that cationic ligands with tethers of intermediate length bound to the P-site, whereas those with long tethers reached the A-site. These binding locations were confirmed experimentally by measuring competitive inhibition constants KI2 for propidium and tacrine, inhibitors specific for the P- and A-sites, respectively. Values of KI2 for propidium increased 30- to 100-fold when ligands had either intermediate or long tethers. In contrast, the value of KI2 for tacrine increased substantially only when ligands had long tethers. These relative changes in propidium and tacrine affinities thus provided a sensitive molecular ruler for assigning the binding locations of the tethered cations.


An interactive simulation environment for craniofacial surgical procedures.
Recent advances in medical imaging and surgical techniques have made possible the correction of severe facial deformities and fractures. Surgical correction techniques often involve the direct manipulation - both relocation and surgical fracture - of the underlying facial bone. The work presented here introduces an environment for interactive, visuohaptic simulation of craniofacial surgical procedures, with an emphasis on both mandibular distraction procedures and traditional orthognathic surgeries. The simulator is intended both for instruction and for procedure-specific rehearsal, and can thus load canonical training cases or patient-specific image data into the interactive environment. A network module allows remote demonstration of procedure technique, a form of 'haptic tutoring'. This paper discusses the simulation, haptic feedback, and graphic rendering techniques used to drive the environment. Particular emphasis is placed on techniques for fracture and subsequent rigid manipulation of bone structures, a key component of the relevant procedures.


Thermodynamic analysis of the stability of planar interfaces between coexisting phases and its application to supercooled water.
Two-phase simulations are commonly used to evaluate coexistence conditions, interfacial tensions, and other thermodynamic properties associated with first-order phase transitions. Calculation of these properties is often simplified when the interfaces between the two phases are flat or planar. Here, we derive a general thermodynamic criterion for selecting simulation cell dimensions to stabilize planar interfaces in phase-separated fluid-fluid systems with respect to homogeneous, single-phase states. The resulting expression is validated by analyzing the effects of simulation cell dimensions on the formation of planar liquid-vapor interfaces in the Lennard-Jones fluid and in the TIP4P/2005 model of water. We also perform large scale molecular dynamics simulations to study metastable liquid-liquid phase separation in the ST2 and TIP4P/2005 models of water under deeply supercooled conditions. Our simulations confirm the stability of a liquid-liquid interface in ST2, and they demonstrate that the corresponding interface for TIP4P/2005 can be stabilized by judiciously choosing the simulation cell aspect ratio in a manner consistent with the thermodynamic criterion. We posit that this sensitivity to the simulation cell aspect ratio may explain discrepancies between previous studies examining liquid-liquid separation in models of supercooled water.


Intellectual impairment in children exposed to polychlorinated biphenyls in utero.
In utero exposure to polychlorinated biphenyls, a ubiquitous environmental contaminant, has been linked to adverse effects on neurologic and intellectual function in infants and young children. We assessed whether these effects persist through school age and examined their importance in the acquisition of reading and arithmetic skills. We tested 212 children, recruited as newborns to overrepresent infants born to women who had eaten Lake Michigan fish contaminated with polychlorinated biphenyls. A battery of IQ and achievement tests was administered when the children were 11 years of age. Concentrations of polychlorinated biphenyls in maternal serum and milk at delivery were slightly higher than in the general population. A composite measure of prenatal exposure was derived from concentrations in umbilical-cord serum and maternal serum and milk. Prenatal exposure to polychlorinated biphenyls was associated with lower full-scale and verbal IQ scores after control for potential confounding variables such as socioeconomic status (P = 0.02). The strongest effects related to memory and attention. The most highly exposed children were three times as likely to have low average IQ scores (P <0.001) and twice as likely to be at least two years behind in reading comprehension (P = 0.03). Although larger quantities of polychlorinated biphenyls are transferred by breast-feeding than in utero, there were deficits only in associated with transplacental exposure, suggesting that the developing fetal brain is particularly sensitive to these compounds. In utero exposure to polychlorinated biphenyls in concentrations slightly higher than those in the general population can have a long-term impact on intellectual function.


Effort-Related Decision-Making in ADHD.
ADHD is defined by behavioral symptoms that are not well characterized in relation to ADHD's neurobiological mechanisms. This approach has limited our ability to define ADHD nosology and predict outcomes because it does not systematically examine facets of the disorder such as the inability to maintain cognitively effortful activities, as promoted in the NIMH RDoC approach. Existing data indicate ADHD is associated with differences in reward valuation and processing, but we do not know whether ADHD is also associated with higher levels of aversion to exerting cognitive effort and/or altered reward x effort interactions. Our ongoing study addresses this knowledge gap by examining individuals' preferences between rewards associated with minimal effort and reward alternatives with a higher payoff but higher effort costs ("effort discounting"); thereby permitting us to characterize differences in biases and tradeoffs during effort-related decision-making in ADHD. The study takes advantage of a well-defined sample of ADHD-diagnosed and healthy control individuals to address three aims. First, we determine whether ADHD is associated with steeper discounting of larger, more effortful rewards. Second, we examine the subjective perception of effort in youth diagnosed with ADHD and healthy controls using tasks requiring varying levels of cognitive effort. Third, we explore relationships amongst indices of effort discounting, theoretically-related traits (e.g., grit, distress tolerance), biomarkers of effort-related decision-making (eye movements and pupil size), and various cognitive measures. Successful completion of the aims will permit us to better characterize ADHD-healthy control differences and lay a foundation for more computational approaches to ADHD diagnostic criteria.


Plant Root-Exudates Recruit Hyperparasitic Bacteria of Phytonematodes by Altered Cuticle Aging: Implications for Biological Control Strategies.
Phytonematodes are globally important functional components of the belowground ecology in both natural and agricultural soils; they are a diverse group of which some species are economically important pests, and environmentally benign control strategies are being sought to control them. Using eco-evolutionary theory, we test the hypothesis that root-exudates of host plants will increase the ability of a hyperparasitic bacteria, Pasteuria penetrans and other closely related bacteria, to infect their homologous pest nematodes, whereas non-host root exudates will not. Plant root-exudates from good hosts, poor hosts and non-hosts were characterized by gas chromatography-mass spectrometry (GC/MS) and we explore their interaction on the attachment of the hyperparasitic bacterial endospores to homologous and heterologous pest nematode cuticles. Although GC/MS did not identify any individual compounds as responsible for changes in cuticle susceptibility to endospore adhesion, standardized spore binding assays showed that Pasteuria endospore adhesion decreased with nematode age, and that infective juveniles pre-treated with homologous host root-exudates reduced the aging process and increased attachment of endospores to the nematode cuticle, whereas non-host root-exudates did not. We develop a working model in which plant root exudates manipulate the nematode cuticle aging process, and thereby, through increased bacterial endospore attachment, increase bacterial infection of pest nematodes. This we suggest would lead to a reduction of plant-parasitic nematode burden on the roots and increases plant fitness. Therefore, by the judicious manipulation of environmental factors produced by the plant root and by careful crop rotation this knowledge can help in the development of environmentally benign control strategies.


Universal H1N1 influenza vaccine development: identification of consensus class II hemagglutinin and neuraminidase epitopes derived from strains circulating between 1980 and 2011.
Immune responses to cross-conserved T cell epitopes in novel H1N1 influenza may explain reports of diminished influenza-like illnesses and confirmed infection among older adults, in the absence of cross-reactive humoral immunity, during the 2009 pandemic. These cross-conserved epitopes may prove useful for the development of a universal H1N1 influenza vaccine, therefore, we set out to identify and characterize cross-conserved H1N1 T cell epitopes. An immunoinformatic analysis was conducted using all available pandemic and pre-pandemic HA-H1 and NA-N1 sequences dating back to 1980. Using an approach that balances potential for immunogenicity with conservation, we derived 13 HA and four NA immunogenic consensus sequences (ICS) from a comprehensive analysis of 5,738 HA-H1 and 5,396 NA-N1 sequences. These epitopes were selected because their combined epitope content is representative of greater than 84% of pre-pandemic and pandemic H1N1 influenza strains, their predicted immunogenicity (EpiMatrix) scores were greater than or equal to the 95th percentile of all comparable epitopes, and they were also predicted to be presented by more than four HLA class II archetypal alleles. We confirmed the ability of these peptides to bind in HLA binding assays and to stimulate interferon-γ production in human peripheral blood mononuclear cell cultures. These studies support the selection of the ICS as components of potential group-common H1N1 vaccine candidates and the application of this universal influenza vaccine development approach to other influenza subtypes.


The projections of intracellularly labeled auditory nerve fibers to the dorsal cochlear nucleus of cats.
The cochlear nucleus receives incoming auditory nerve discharges, preserves or transforms the signals, and distributes outgoing activity to higher centers. The organization of auditory nerve input to the cochlear nucleus will heavily influence the mechanisms by which acoustic information is processed. In order to study structure-function relationships between auditory nerve and cochlear nucleus, the axonal arborizations of type I spiral ganglion cells were labeled with intracellular injections of horseradish peroxidase after first being electrophysiologically characterized by recording with a micropipette inserted into the axon. For each auditory nerve fiber, spontaneous discharge rate (SR) and a frequency tuning curve were determined. The tuning curve yielded the characteristic frequency (CF, that frequency to which the fiber is most sensitive) and CF threshold in dB SPL. Individual axonal arborizations including all terminal swellings were reconstructed through serial sections with the aid of a light microscope and drawing tube. On average, 13.4 +/- 8.1% of the terminal swellings were found in the dorsal cochlear nucleus (DCN) and the remaining terminal swellings were located in the ventral cochlear nucleus. In the DCN, the terminal fields of auditory nerve fibers were restricted to layer III, contributed to cytoarchitectonic striations, and exhibited a systematic relationship between fiber CF and position along the strial (or long) axis of the nucleus. Computer-aided rotations revealed that the terminal fields were anisotropic, being flattened within the trans-strial axis. The maximal width of the terminal fields along the strial axis ranged from 31-321 microns and was inversely related to fiber CF and SR. Variation in the number of terminals or depth of the terminal field within layer III was not related to SR grouping or CF of the fiber.


Quantifying data quality for clinical trials using electronic data capture.
Historically, only partial assessments of data quality have been performed in clinical trials, for which the most common method of measuring database error rates has been to compare the case report form (CRF) to database entries and count discrepancies. Importantly, errors arising from medical record abstraction and transcription are rarely evaluated as part of such quality assessments. Electronic Data Capture (EDC) technology has had a further impact, as paper CRFs typically leveraged for quality measurement are not used in EDC processes. The National Institute on Drug Abuse Treatment Clinical Trials Network has developed, implemented, and evaluated methodology for holistically assessing data quality on EDC trials. We characterize the average source-to-database error rate (14.3 errors per 10,000 fields) for the first year of use of the new evaluation method. This error rate was significantly lower than the average of published error rates for source-to-database audits, and was similar to CRF-to-database error rates reported in the published literature. We attribute this largely to an absence of medical record abstraction on the trials we examined, and to an outpatient setting characterized by less acute patient conditions. Historically, medical record abstraction is the most significant source of error by an order of magnitude, and should be measured and managed during the course of clinical trials. Source-to-database error rates are highly dependent on the amount of structured data collection in the clinical setting and on the complexity of the medical record, dependencies that should be considered when developing data quality benchmarks.


The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment.
The BRCA2 gene was identified based on its involvement in familial breast cancer. The analysis of its sequence predicts that the gene encodes a protein with 3,418 amino acids but provides very few clues pointing to its biological function. In an attempt to address this question, specific antibodies were prepared that identified the gene product of BRCA2 as a 390-kDa nuclear protein. Furthermore, direct binding of human RAD51 to each of the four single 30-amino acid BRC repeats located at the 5' portion of exon 11 of BRCA2 was demonstrated. Such an interaction is significant, as BRCA2 and RAD51 can be reciprocally coimmunoprecipitated by each of the individual, specific antibodies and form complexes in vivo. Inferring from the function of RAD51 in DNA repair, human pancreatic cancer cells, Capan-1, expressing truncated BRCA2 were shown to be hypersensitive to methyl methanesulfonate (MMS) treatment. Exogenous expression of wild-type BRCA2, but not BRC-deleted mutants, in Capan-1 cells confers resistance to MMS treatment. These results suggest that the interaction between the BRC repeats of BRCA2 and RAD51 is critical for cellular response to DNA damage caused by MMS.